U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

ADVISORY COMMISSION ON CHILDHOOD VACCINES (ACCV)

December 9, 2011

Parklawn Building

5600 Fishers Lane

Rockville, MD

Proceedings by:

CASET Associates, Ltd.

Fairfax, Virginia 22030

(703) 266-8402

CONTENTS

Welcome and Unfinished Business from Day One 1

Ms. Sherry Drew, Chair

DVIC Clinical Update/Institute of Medicine 1

Report generated Task Force Update

Dr. Rosemary Johann-Liang,

Chief Medical Officer, DVIC

Intussusception: Proposal to add to the Vaccine 7

Injury Table for rotavirus Vaccines

Ms. Anna Jacobs, Office of General Counsel

Update on the Immunization Safety Office (ISO), 68

Centers for Disease Control and Prevention

(CDC) Vaccine Activities, Dr. Tom Shimabukuro, CDC

Update from the National Vaccine Program 75

Office (NVPO), Dr. Dan Salmon, NVPO

Update on the National Institute of Allergy 77

And Infectious Diseases (NIAID), National

Institutes of Health (NIH) Vaccine Activities,

Dr. Barbara Mulach, NIAID, NIH

Update on the Center for Biologics, Evaluation 79

And Research (CBER), Food and Drug Administration

(FDA) Vaccine Activities, Lt. Valerie Marshall,

CBER, FDA

Nomination/Election of New Chair and Vice Chair 81

Ms. Sherry Drew, Chair

Future Agenda Items, Ms. Sherry Drew, Chair 83

Public Comment 90

Adjournment of the ACCV December 92

Quarterly Meeting

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P R O C E E D I N G S (9:00 A.M.)

Agenda Item: Welcome and Unfinished Business

from Day One, Ms. Sherry Drew, Chair

MS. DREW: Good morning. Welcome to our meeting.

We reported the number of Commissioners that were here

yesterday. We are all here again today, other than

Michelle Williams, who will be slightly late. I am

wondering if we have any unfinished business from yesterday

that anyone would like to raise.

There being no unfinished business, we will move

onto Dr. Rosemary Johann-Liang, DVIC, Clinical Update on

the Institute of Medicine Report, Generated Task Force

Update.

Agenda Item: DVIC Clinical Update/Institute of

Medicine Report Generated Task Force Update, Dr. Rosemary

Johann-Liang, chief Medical Officer, DVIC

DR. JOHANN-LIANG: Good morning everybody. The

way the agenda has it s that I’m going to be talking about

IOM and other folks will be talking about rotavirus. We’re

going to be actually doing this all together.

You know, when we usually do the every three

month update, I give you guys a quarterly update on the

medical review and analysis, going over how many claims

came in, what the claims were about, what were the

vaccines, some interesting issues, et cetera.

2

But because we have an hour and a lot of slides

to cover, and some thinking involved this morning, I am

going to just do that next time, and we’ll bring it

together and give you guys an updated review of the medical

update. Today I want to just give you a brief update on

the IOM report.

Remember, last ACCV, when you guys met, Dr.

Clayton, the Chair for the IOM Committee, gave you guys a

full briefing on the report. I believe everybody received,

the ACCV members, and I know we have new members, so we’ve

got to get, Annie, we’ve got to get the pre-pub copy to

them as well. We have ordered the IOM hard copy. It

comes in a book for all of you at the ACCV.

But they apparently take a long time going

through their editing and copying thing and going to

wherever the books go to get bound, et cetera. And so it

probably will be some time in the spring that those books

will be available for everyone. So we’ll make sure that

everyone has a pre-pub copy available. That’s what we are

working off as well for now until we have the full

publication available.

I am going to just give you a little bit of a

background, because we have some new members joining, and

then give you an update of where we are with this. And

then the most of this hour we want to spend on the

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rotavirus vaccine and intussusception and proposal for

changes to the injury table.

I am going to be doing that with my colleagues

from the rotavirus Vaccine Working Group. As it turned

out, we really did not plan this, we are all in sort of

black and red today. So you can see that we’re all

synchronized in our thinking. It’s government at its best.

The members from the working group who will be

speaking today will be Ms. Anna Jacobs. She is our Office

of General Counsel, Counsel to our VICP, and member of our

working group. And Dr. Mary Rubin, who is a pediatrician

and one of the medical officers in our division.

So let’s just talk about IOM vaccine adverse

event review history. The contract actually to the IOM

started in the fall and the winter of 2008. It took some

time to get all the paperwork in order for them to look for

the committee members that would be totally no conflict of

interest, et cetera.

And so it took until April of 2009 for us to meet

the committee, the initial committee, and give them the

charge from the government as to what we would like for

them to do. And really, this was the first time, I think,

it was a HRSA-generated IOM contract.

There were a number of vaccines that had been

added to the table that had no adverse events listed on

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them. Our goal was to really try to get an outside

independent assessment of the current science so that we

can update the injury table.

And to do so, we asked them not only to look at

certain vaccines and certain adverse events, but to really

give us some sort of a framework of doing causality

assessments, because there are many different ways people

look at causality, but it was really important for us to

all work by the same sort of framework.

And even after IOM was done, there are other

vaccines that we just couldn’t ask them to review, because

there are only limited funds. So we would need to go back

and do some of that causality assessment for other

vaccines, other adverse events. We really wanted to know

what framework to work off of. That was a really major

issue.

But then we also gave them a list of adverse

events that really were generated by us talking to our

sister agencies throughout the government, especially CDC,

the Immunization Safety Office, where we are currently

working with.

The list of adverse events was generated for four

vaccines initially. Mainly the criteria for why those four

out of the 16 that we have covered in the program, is

because those were ones that were newer, that did not have

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adverse events listed. And then thirdly, really, the

vaccines that had a lot of claims coming into our program

and there was media attention.

So the initial ones were really varicella, which

was added a long time ago, but there was nothing listed on

the table, influenza, which was a big vaccine in the sense

that we were getting a lot of claims, meningococcal and

HPV, because these were newer vaccines. That’s all we had

resources for.

And then thankfully, after the initial charge

went out we were able to get additional funding through the

ARRA stimulus funding through CDC, and add four more

vaccines for review. And this was really fortuitous

because it only needed a little bit of resources to add

more vaccines, because the sitting of the committee is what

was so costly.

And then after all of that, the final release of

the report was this August. You all heard the presentation

by the Chair in the last ACCV. So these were the vaccines

that were reviewed. And they were reviewed together. It

shows that it really makes up 92 percent of VCIP claims.

So we thought that was really helpful for us to get a good

sense of how we can go and modify the Vaccine Injury Table.

Remember that the working list of adverse events

were generated from our staff, based upon our statistics,

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and what the current science as we understood they were.

And then we presented it publicly during the charge, and

IOM put the working list up on their website, so it was

open to the public. And the public had all of that time to

add their comments and their recommendations to the list.

The IOM was not going to take away anything that

we had asked for, but they were open to, and they did, add

further adverse events to the list. And because this is

really supposed to be an independent review by them, we

gave them a general concept. It was really up to them to

figure out the framework and how they were going to put the

adverse events together, and what the final list and the

final review was going to be.

As you saw from the report, the final working

list constituted 76 different adverse events, 157 adverse

event vaccine combinations. So as you saw on the report,

they had the causality framework as we asked them, as we

charged them, with a three-pronged approach. They looked

at not only the weight of the epidemiologic evidence, at

the four levels, but also the weight of the mechanistic

evidence, and they put that together for an overall

causality assessment.

And the conclusions that they had also were in

four different categories, and it lists here what

convincingly supports, what favors acceptance, what is

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inadequate to accept or reject, and then what favors

rejection. Those were causality conclusions. We will

really spend a lot more time on this once we bring what our

thoughts are, based upon their review, before you.

Currently, the members of the HHS, the Task Force

for this, which constitutes Immunization Safety Office, our

Office of General Counsel and HRSA reviewers, are working

very hard. So everything is under review. Our goal is, at

the risk of being called a taskmaster, our goal is to

really try to at least bring the initial thoughts before

you for the next ACCV meeting.

The nine working groups –- it is the eight

vaccines, but we also have a general category which we

charge the IOM for, which is the actual injection and

administration adverse events. That is the ninth category,

and that is what we are all very, very busy working on

right now.

I’m going to just move right along unless

somebody has a burning question about the first part of

this. So rotavirus -- I’m going to actually ask my

speakers here to come up and join me, and then we can do

this as a team. This is Anna Jacobs and Mary Rubin, and we

are going to be talking to you about rotavirus vaccines and

intussusception.

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Agenda Item: Intussusception: Proposal to Add to

the Vaccine Injury Table for rotavirus Vaccines, Ms. Anna

Jacobs, Office of General Counsel

DR. JOHANN-LIANG: Now this is something you have

heard a lot of, because we have kept you abreast as we have

learned things too, as to what we are doing. But we have

come to a time where we are actually going to ask you what

your thoughts are.

I want to make sure that all of you in your

binders have not only the slide set but the proposed reg.

Do you have all that? And the voting folks are eight, and

Michelle, nine, right? So if you can make sure that you

have the regs with you. It is the one that looks like a

lawyerly kind of thing. It has the table, it has a little

blurb and there is a table. It is really important that

you guys all have the regs with you.

So the IOM did not include –- we did not ask them

to include the rotavirus because at the time when we gave

the charge, rotavirus issues were pretty quiet. So we only

could ask them to get the big ticket items at that time.

But as the IOM review was ongoing, we had some

recent post-marketing surveillance publication come up,

which led us to establish our rotavirus working group and

the intussusception issue. And today we are finally

proposing a draft regulation regarding this adverse event.

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So these are the members of our working group.

Dr. Shaer is sitting here as well. And Dr. Smith, I

believe is on an open line. Remember, she is the one that

gave you guys a very comprehensive talk on rotavirus and

all of that data, preclinical, the thoughts about the

shedding and all that which we don’t have time to go into

today. I am just going to briefly just give you a summary

so that we can all come to speed.

The outline is that Anna Jacobs is going to give

you some of our legal history and what ACCV came up with

some years ago, the Guiding Principles about how we go

about changing the Vaccine Injury Table.

I will summarize some of the data because that

has already been extensively discussed. And then Dr. Rubin

will talk about there is an ongoing study in the US right

now that I think it is important that you guys know that

that is ongoing. And then the actual proposed changes to

the table. I will come back, summarize and ask you guys

what your thoughts are.

We may need a little bit of a -– this is a really

good practice going into the IOM. We may need to figure

out a little process issue of how we are going to query the

members for their input.

rotavirus disease, just to start off, is very

common. I am sure that if you have young children, most

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young children have rotavirus. In the winter months is

when it comes the most. They have vomiting, fever,

gastroenteritis, and almost everyone gets this by age five.

The mortality is not such an issue in the US, but

in developing countries there are many deaths actually

caused from this due to dehydration, et cetera. And even

in the US there are many rotavirus induced, disease-induced

hospitalizations. Although now with the vaccinations in

place the hospitalizations are decreasing.

Then, talking about what intussusception is, the

picture is worth a thousand words, right? It shows you how

one segment of the bowel sometimes, for various reasons,

actually sort of telescopes into the next segment of the

bowel. You can imagine all those blood vessels sort of get

pulled with it. And so you start to get less blood flow,

and then swelling of the gut. And then eventually you will

actually get obstruction and the child can really get into

trouble.

It is quite uncommon, the intussusception part.

It is about 1,400 kids in the US per year. Just so that we

can have a common denominator for you to put things into

context, that translates to something in the US on the

order of like 30 to 60 cases per 100,000 kids per year.

PARTICIPANT: That’s pre-rotavirus. That’s just

the baseline incidence.

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DR. JOHANN-LIANG: This is background, background

incidence of intussusception, so just so that you can put

it in the context of intussusception, what the numbers look

like when you have the RotaShield, which Anna is going to

talk about. And then I will come back and talk about what

the numbers are with the second generation rotavirus

vaccines, because I think it’s important for you guys to

know the magnitude of the issue.

So you don’t really see this too much in little,

little babies. It really sort of starts to peak about,

earliest maybe at two months, and it goes up to peak at

like six months. You can have intussusception even in an

older child, but the peak really is that the babies, when

they are really cute, you know that four to six months,

that time. It is really pathetic when they -–

So naturally occurring -- there is a little bit

more information. So this is intussusception as a

baseline. It is interesting that this adverse event really

varies by region. For example, you are going to see the

new study that was published in Mexico and South America.

Even as a background, in South America the incidence of

this adverse event, intussusception, is much higher, on the

order of doubling what we see in the US.

So there are region variances. And Mary is going

to talk about all the different issues of why IS occurs

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naturally, without the vaccine. It is usually diagnosed

with, if you have stool that is we call currant jelly

stool, you have the diagnostic thing right there

clinically.

But sometimes you need to use radiological tests

to diagnose it, which we do with the barium contrast. But

also just putting the barium through sometimes reduces and

actually corrects for the intussusception. That is

different than children who actually end up having surgical

intervention.

It seems that the data shows it really is not

that there is any difference between these kids. But if

you don’t treat or reduce the telescoping with the barium

or by natural happenstance –- I remember having a patient,

getting them through the ambulance. We hit a pothole –-

boom, the pothole hit, the kid reduced. So you can have a

natural reduction. But usually you need a barium

reduction.

But if you don’t get to the child, and you end up

-- yes, I got a standing ovation when I got off the

ambulance -– but when you don’t get to reducing them, then

they can go on in their disease. And you can see that the

more you obstruct, it just becomes to a point where the

child has to undergo surgery, and the surgical

intervention.

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So that is the different way to treat it. It

looks like it’s about 50/50 in how the patients get treated

with this illness. So morbidity and mortality from this

adverse event is very low in the US, just like rotavirus

mortality is very low in the US. And recurrences do

happen. I am going to turn now over to my colleague here.

MS. JACOBS: I am Anna Jacobs, and I am an

attorney with the Office of the General Counsel, and I

advise the VICP with Elizabeth Saindon, my colleague.

Today I will just go over again the basics of the Vaccine

Injury Table and how that is revised and what your role is

in all of this. And then we will walk through the history

of rotavirus as it relates to the table and the program.

So as you are well aware, the program has a

Vaccine Injury Table, and claims that fit within the

parameters of the table receive a presumption that the

vaccine caused the injury. And the petitioner is entitled

to compensation unless the government can prove that

something else caused the injury.

And so if the claim does not fit within the

parameters of the table, then the petitioner can receive

compensation if he or she proves that the vaccine did in

fact cause the injury.

And so how do you fit within the parameters of

the table? The petitioner has to prove three things. The

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petitioner has to prove that she received a vaccine set

forth in the table, sustained or significantly aggravated

an injury listed on the table in association with that

vaccine, and sustained the injury, or the onset of the

injury occurred within a time frame listed on the table.

And so the injuries are defined in a section that

is called the qualifications and aids to interpretation.

And the statute says the following qualifications and aids

to interpretation shall apply to the Vaccine Injury Table.

We also call them the QAI.

And so Congress recognized that science is not

static. It changes. And so they wanted the table to also

be able to change along with science. But they didn’t want

to leave that up to the legislative process because the

legislative process moves a lot slower than science does.

So they gave the Secretary the authority to change the

table by way of the regulatory process.

So by regulation, the Secretary can modify the

table by adding or deleting vaccines, adding, deleting or

modifying injuries. And that includes the definitions of

those injuries. And can also change the time periods

listed and add those.

And that regulatory table is found in the Code of

Federal Regulations in Title 42 in Part 100.3(a). And so

by statute modifications to the table apply only with

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regard to petitions that are filed after the revision.

Just to go through the general basic process of

the regulatory process, basically, the Secretary would

publish a Notice of Proposed Rulemaking, and then the

Secretary would have to afford at least 180 days of public

comment and provide a public hearing on the proposal. And

then after that period closes the Secretary can move

forward with publishing a final regulation.

What is your role in all of this? The Secretary

cannot propose a regulation until she first provides you

with a copy of the proposed reg text, which is what you

have before you in your materials, and requests comments

and recommendations, and affords you at least 90 days to

come up with a recommendation.

So what standard should guide you in considering

the proposal? Unfortunately, there isn’t a whole lot set

out in the statute. The statute does give a standard for

when the Secretary should add a vaccine to the table. And

the Secretary should do that when the CDC recommends a

vaccine for routine use in children, the Secretary shall

add that vaccine to the table within two years. But there

is no standard for adding injuries, modifying or deleting

injuries.

And so, in 2006, the ACCV at that time developed

a set of Guiding Principles. And I believe you also have

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this document in your materials, and you are welcome to

pull that out. I am going to just walk through them and

summarize them for you. I should say these principles are

not legally binding on you. They are just helpful, it’s a

helpful set of guidelines that you are welcome to use.

So in essence, the ACCV then believe that the

table should be scientifically and medically credible, and

where there is credible scientific and medical evidence,

both to support and reject a proposed change, then the

change should really tend toward benefiting the

petitioners.

So what is scientifically and medically credible?

The ACCV said that conclusions in IOM reports are deemed to

be credible, but of course that should not limit your

discussions. For data sources other than IOM reports, you

will need to assess the relative strength of the evidence.

Consistency across multiple sources is an indication of

strength of the evidence.

And so they set out a hierarchy of data sources

ranging from the strongest sources to the weakest sources.

And I won’t go through all of them, but the strongest

sources are going to be the clinical laboratory data,

challenge/re-challenge data involving non-relapsing

symptoms or diseases in controlled clinical trials. And

the weakest source is going to be more like your case

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reports, editorial articles on scientific presentations and

non-peer reviewed publications.

And also consider whether there are

methodological limitations in the studies, is there any

potential bias or confounding factors, and is there

biologic adherence in the conclusions.

Do not worry, though, if you are not a scientist

and you don’t regularly assess the strength of evidence,

because you are welcome to seek the assistance from the

Division of Vaccine Injury Compensation. And you can ask

them to guide you through the evidence to help you assess

the strength.

And of course, the ACCV recommended that you

should remain aware of the policy considerations underlying

the table. Congress basically intended that awards to

vaccine injured persons should be made quickly, easily,

with certainty and generosity. And they also intended to

compensate the very serious injuries. And so if there is a

perfect split down the middle in the evidence, then you

should tend toward adding or retaining the injury.

So now I’m going to walk through the history of

rotavirus in the program as it relates to the table.

Rotavirus vaccine is not new. On August 31, 1998, the FDA

licensed the live, oral, rhesus-based rotavirus vaccine,

and that was under the trade name of RotaShield. This was

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the only US-licensed rotavirus vaccine on the market at

that time.

And so the CDC then recommended this vaccine be

routinely administered to children, and so on October 22,

1998, the Secretary added the general category of rotavirus

vaccine to the table, with no condition specified, or no

timeframe. So around this time, VAERS had been receiving

reports of intussusceptions occurring after the first dose

in infants.

So July 16, 1999, the CDC then recommended that

parents and health care providers suspend the use of

RotaShield, and they continued to conduct studies to

determine an association. And the manufacturer voluntarily

ceased distribution of RotaShield. And then on October 15,

1999, they voluntarily withdrew the vaccine from the market

and requested immediate return of all doses.

Shortly after that, October 22, 1999, the ACIP

concluded that intussusceptions occurred with significantly

increased frequency in the first 14 days following the

administration of RotaShield, and withdrew their

recommendation for use of RotaShield in infants, and the

CDC adopted that as their recommendation.

And so in 2001, July 13, the Secretary published

a Notice of Proposed Rulemaking to revise the table. And

the Secretary found that intussusceptions could reasonably

19

be determined in some circumstances to be caused by

vaccines containing live, oral, rhesus-based rotavirus.

The Secretary proposed to add a specific category

of vaccines containing live, oral, rhesus-based rotavirus,

with the associated injury of intussusception with a

timeframe of zero to 30 days. The Secretary then published

the final rule on January 25, 2002, and it became effective

on August 26, 2002.

And so basically, what the table then looked like

was, there was this general category of rotavirus vaccines,

no conditions specified and no time frame. And there was

also this specific category of live, oral, rhesus-based

rotavirus vaccine with injury of intussusception, with a

timeframe of zero to 30 days.

And that injury only applied to vaccines

administered on or before the effective date of the

regulation. And you will recall, though, that the vaccines

had been long since withdrawn from the market, and they

weren’t being distributed.

So if you fast forward then to October 9, 2008,

the Secretary removed then the specific category of

vaccines containing live, oral, rhesus-based rotavirus and

the associated injury. And her reasoning for this was that

RotaShield was removed from the market on October 15, 1999,

and the CDC withdrew their recommendation for routine use

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of the vaccine shortly after that.

So really the claims could likely only been for

injuries sustained from vaccines that were administered

before that time, because they were not being administered

after that time.

So if you take that into consideration, and the

fact that the table required the injury to have occurred

within 30 days after the vaccination, and you consider the

statute of limitations, which in the case of table

revisions, for injuries that occurred before the revision,

the petitioner has two years to file a claim, and the onset

of the injury needed to have occurred within eight years

preceding the revision.

So doing the math, if the date of table revision

was August 26, 2002, then the date that the last claim

could have been filed would have been August 26, 2004. And

the onset of injury or the death needed to have occurred

between August 26, 1994 and August 26, 2002.

But that filing deadline of August 26, 2004 is

the key date. And so by 2008, the Secretary believed that

any potential claim under this specific table category

would have been time barred. But the Secretary did retain

the general category of rotavirus vaccine with no condition

specified, no timeframe.

And that is where we are today. And I will turn

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the platform over to my colleague, Ro.

DR. JOHANN-LIANG: Ro needs to speak very fast

because we are in a time crunch here. This is a slide that

you all saw already. I believe this was given to you –

update 3/20/11, it must have been in March. I say it right

up there on the slide here. March you got this slide. And

what I tried to do here was, because you did get an

extensive review from, I believe, the FDA representative in

October 2010, when all of this was being presented to ACIP.

I just did a summary slide for you at that time,

showing what the difference between the RV1 and RV5 is, and

then what pre-licensure studies showed. So the way the

pre-licensure studies for these second generation vaccines

were powered, the numbers needed was based upon what they

saw with RotaShield.

If the RotaShield was -– if they thought there

was maybe one in 11,000 they wanted to rule that out, and

that is why it was powered to have about 30,000, 35,000.

That is a huge safety study. As a pre-licensure study

goes, you just don’t see that, and that is why you see the

numbers like that. And really, there was nothing seen, so

it was ruled out for IS, for intussusception.

And the post marketing, remember, you have seen

all this before, and I’m going to go over this again. But

this is what was shown to you in March as a summary slide,

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and then in June, the New England Journal publication came

out about the South American studies.

And what they showed was a slight increase in

attributable, meaning there is a background. And remember

I told you, there’s more of intussusception down in South

America. But on top of that, they also thought there was a

little bit of an attributable risk from the vaccination,

mainly with the first dose, one to seven days post the

first dose.

And there was a commentary also written about

this, talking about the background of RotaShield. Really,

for safety we look at the totality of the evidence, all the

different things, the background, what is happening. It is

kind of like that kind of editorial.

So given this coming out in June, this is a

further updated slide of what you saw before. And I just

took out the pre-licensure and expanded on the post

marketing a little bit. So that study, the Patel, et al,

from the New England Journal, was Mexico, the incidence

rate of 5.3, one to seven days after first dose, not after

dose two.

In Brazil a little bit different. And Dr. Smith

went through this with you last time. It was actually

after dose two, not after dose one. Again, one to seven

days after the vaccine. And the thought behind it, nobody

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really knows but the thought behind that is that in Brazil

oral polio is co-administered. And the thinking was that

the oral polio -- and I guess what is happening in your gut

may take precedence over what needs to happen

immunologically for rotavirus vaccine.

So it is not really until dose two that you see

this effect, that small attributable risk on top of -- and

then also for Rotarix. And when we talk about Rotarix

right now, there is the Australian surveillance which

looked at what was happening with the kids against the

expected. So it is not a concurrent control, it is really

an expected number.

And they did a relative risk and then again saw

something a little bit above one to seven days post after

first dose, and not after second dose. That is Rotarix.

RotaTeq, the data is even not -- the issue is, Rotarix is

where we have better data. I think there is a little bit

of an attributable risk.

It is really in the order. If you think about it

like this. So baseline is something like 30 to 60 in the

US per 100,000. So the RotaShield was really like an

additional five to 10 cases per 100,000. For these second

generation vaccines, very simply, probably if there was

something there, something in the order of one or two extra

cases per 100,000.

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We are talking about much lower magnitude of

attributable risk. But it looks like for Rotarix, because

you have seen it in a couple of different places outside of

the US data, that something is really there. RotaTeq is a

little bit difficult because the only thing we really have

is the article by Buttery et al. in Vaccine that talks

about, again, the Australian data.

We don’t really have anything that is what we

call a positive study in the sense of an attributable risk

in the US at all. And RotaTeq is actually the vaccine that

is being most utilized in the US. Now I am told by CDC

that Rotarix will have an uptake, and we will see Rotarix

use in the US as well, moving into the future. But

currently it is really RotaTeq that we use in this country.

Dr. Rubin is going to talk about because of this,

because this is uncertain data sets and there is really

nothing in the US, the FDA has started a study on this

issue. And she will talk about this.

DR. RUBIN: Good morning, everybody. Again, my

name is Mary Rubin and I am a pediatrician. And I work as

a medical reviewer at DVIC. I know the important thing is

the proposal, but I will first discuss the ongoing study

which is part of the FDA’s Postlicensure Rapid Immunization

Safety Monitoring program, which is PRISM.

PRISM was actually established as one of the

25

several 2009 H1 influenza vaccine safety surveillance

efforts. And then PRISM was incorporated into the mini

Sentinel to focus primarily on vaccines. The mini-sentinel

is one piece of the Sentinel Initiative, which is a multi-

faceted effort by the FDA to develop a national electronic

system that will complement existing methods of safety

surveillance.

So this PRISM study on rotavirus vaccines in the

US will assess the risk of intussusception after Rotarix

and/or RotaTeq vaccines. So this is actually both the

second generation rotavirus vaccines.

Now a detailed protocol is found in the mini-

sentinel website, which is on www.mini-sentinel.org, for

those people on the phone. It is also on the slide set.

This analysis will use what is usually used in the Vaccine

Safety Datalink studies. Self-controlled, case centered

and sequential methods. And the total study population is

estimated to be greater than one million infants, during a

maximum study period of January 2004 to a point in 2011

that is undetermined

The investigators are hopeful to have preliminary

results by the fall of 2012. So this data is not available

to us right now. But based on the available data, which I

will go back to Dr. Johann-Liang’s slide, as you can see

the increased rate of rotavirus intussusception, there is a

26

small increased rate within one to seven days after the

first dose. And most of the data that is available is with

Rotarix vaccines.

So we will go back to our proposal. We do

propose amendment to the general category of rotavirus-

containing vaccines, which involves the injury of

intussusception, with a time period of zero to 21 days.

Now as the publications show, one to seven days is the risk

window. And we are proposing zero to 21 days, to be

consistent with the ACCV Guiding Principles. As Ms. Jacobs

mentioned earlier, RotaShield intussusception data showed a

one to 14 days window. And the Vaccine Injury Table listed

zero to 30 days for that rotavirus vaccine.

So what is intussusception? I know you have

heard a lot about it already. But intussusception, as

Rosemary, Dr. Johann-Liang mentioned, is the invagination

or telescoping of the proximal segment of an intestine into

the distal segment of the intestine. This can result in

obstruction of the bowel passage, constriction of the

mesentery and obstruction of the venous blood flow.

This can be characterized by sudden onset

abdominal pain. As Ms. Jacobs mentioned, there is a

section in the Code of Federal Regulations, that the

following Qualifications and Aids to Interpretation shall

apply to the Vaccine Injury Table, to paragraph A of the

27

section and Code. So we are proposing to add this

paragraph that defines the injury of intussusception.

This slide is actually just a snapshot of the

specific Vaccine Injury Table line. But you have the full

Vaccine Injury Table with the regs in your handouts. So it

just shows the vaccines containing rotavirus and injury

intussusception in zero to 21 days.

Now in addition, the proposed paragraph for

Qualifications and Aids to Interpretation, or QAI, as I

will call it from now, gives presumption of causation to

intussusception occurring after the first or second dose.

As publications show, association after the first dose.

And actually, some of the studies of RotaTeq show that the

third dose is protective, or does decrease risk, and in the

absence of alternate factors.

Now while in most intussusceptions, the cause is

unknown, a proportion of naturally-occurring

intussusceptions have been associated with infectious

disease, conditions causing lead points, anatomic

abnormalities and underlying conditions or systemic

diseases.

I will discuss each of these factors in a little

more detail in the following slides. And for each section

you will find references to articles of medical literature.

The credits go to Dr. Chris Liacouras, who is the Pediatric

28

Gastroenterologist from the Children’s Hospital of

Philadelphia, for literature review and reference.

So infectious disease secondary to both enteric

and nonenteric strains of adenovirus enterovirus, and other

viruses are linked to intussusception, as well as bacterial

enteritis such as those due to campylobacter or salmonella

typhi, as well as parasitic diseases such as ascaris, could

be examples.

Intestinal masses like polyps and tumors and

cystic structures like Meckel’s diverticulum and

duplication cysts, and also increased lymphoid tissues such

as lymphoma, may actually protrude into the intestine, or

create a weakness in the wall. So these can act as what is

called lead point, which causes the intussusception.

And then congenital anatomic abnormalities such

as malrotation, anatomic changes after surgery, and

abnormal intestinal blood vessels such as hematoma or

hemangiomas are also attributable factors.

Finally, systemic illnesses such as inflammatory

bowel disease, namely Crohn’s Disease and ulcerative

colitis, also cystic fibrosis and celiac disease have been

associated with intussusception. As an example, in cystic

fibrosis the stools in these patients can become very

dehydrated and putty like in consistency, and adhere to the

bowel wall. And this actually can act as a lead point.

29

Also, there are other conditions that have small

vessel tissue inflammation, which have been associated with

intussusception as well, such as Henoch-Schonlein purpura

and Kawasaki disease. So putting all of these together,

here is a slide of the proposed language of the QAI, which

you also have in your handout. I guess I will stop here.

DR. JOHANN-LIANG: You guys all have this in

front of you? This is the Qualifications and Aids at the

bottom of the proposed regulation change. And basically

Dr. Rubin just went over the definition of intussusception.

And that is followed by, basically this is laid out as what

really doesn’t qualify to give you presumption of causation

under the table if you have a baby with an intussusception.

So that is what you have before you.

I am just going to go on to just give you an

update. I gave you an update about so what does it mean

for our program really, to kind of put that in perspective.

The last time we met I believe I gave you a brief synopsis

of 12 cases that we had gotten claims for. That number is

up to 15 now, at the end of fiscal year 2011. These were

15 RotaTeq intussusception claims.

And this is sort of a demographic breakdown, 11

males, four females, age range from eight to 31 weeks, and

you can see that these are all you would see in the

background IS population. And it breaks down really, there

30

are five after dose one, five after dose two, and five

after dose three. That is how it broke down.

And many of these children really did have

serious sequelae in the sense that they ended up in the

hospital and had to actually undergo surgery. Eighty

percent actually have surgical intervention, not just

barium enema. And about half of them had -- if you look at

the listings in the QAI that Dr. Rubin was going over --

about 50 percent of those kids actually had one of those

qualifications for alternate factors. That is kind of what

we have.

So this is not by any means the flu generated

claims that we see. This is a small percentage of what we

are reviewing in the program. But certainly given the new

information, and under really the Guiding Principles that

Ms. Jacobs went over, we really felt that we wanted to

proactively bring this before you and propose a regulation

change.

So in summary, some but not all studies suggest

the possible very low risk of intussusception caused by the

second generation rotavirus vaccines, mainly the studies on

Rotarix. And it is after the first dose, within the one to

seven days post-window.

The level of observed risk, I talked about the

numbers with you and sort of gave you a side by side

31

comparison background to what we saw on RotaShield and what

we are seeing with the second generation rotavirus

vaccines. And possibly, if there really was an

attributable risk, there will be an additional one case per

100,000 infants.

We do know that the benefits continue to outweigh

the risk, and so the rotavirus vaccines are still being

recommended by CDC, by ACIP. It is a very different story

than what RotaShield attributable risk was shown at that

time in the history you heard from Ms. Jacobs.

So given, as I said, the background of the

RotaShield experience that we had in intussusception, given

the new intussusception information, mainly coming from

literature inside of the United States, but given that we

have the Guiding Principles which you already have, this is

what we are proposing.

Keep in mind, though, as Dr. Rubin went over,

there is a study that is ongoing right now, and it is a US

study, the PRISM study. So we don’t know what the answers

are to that yet. That’s an unknown. We also gave you the

hard copy of the proposed regulation changes, because that

is what the statute requires for the ACCV members to have.

And we also are asking you for your recommendation.

And the choices are as follows as to what we want

to do with the proposed regulation. You can concur with

32

the proposed amendment to the table. And what that would

mean is that we would bring together a Notice for Proposed

Rulemaking, NPRM, which we have already started to draft.

And we have to get that out to the public. There will be a

six-month comment period for the public to give their

input, and then we can move ahead to a final rule. That is

what number one is.

Number two is that you don’t concur with the

proposed amendment and you don’t want to move forward, you

don’t think there is enough evidence here, you think that

the numbers of claims coming into the program are not that

much. I don’t know what your reasons are, but that would

be one choice.

Number three would be you have the regulation in

front of you and you want to think about it, sleep on it,

and you want to make recommendations to changes for the

next meeting. That’s a choice.

And number four, because we have this US PRISM

study that is ongoing right now, that you would like for us

to wait until the data from that study is final. Which we

think that at best the preliminary answers will be end of

next year, 2012, and then the final answers probably won’t

be until sometime in 2013. It takes forever for the end

product of publications to come out. I don’t know, it

depends. But it’s some time to go. But that is a choice

33

you have.

Keep also in mind that from the summary that Dr.

Rubin was showing you, the denominator is about a million

there, too. And I am not quite sure how much of that is

going to be Rotarix or RotaTeq. And remember, in the US,

Rotarix is just not used. So even if you were to try to do

the study, you can’t really get the charts to review

RotaTeq, so depending on how the denominators for those two

vaccines work out, we are not quite sure, because the VSD

study was also approaching a denominator of about a

million. And they didn’t see anything.

So at the end of the day you may be still left

with, we don’t see anything here but our denominator is

still just right there. So I am not quite sure. If we

thought, if the working group thought that this was a

definitive study that would give us a definitive answer in

the United States, we may make that a choice number one and

say let’s just wait. This is what we have now, we are

going to continue to wait for the answers to come in and

adjudicate claims as they come in.

But given that we are not quite sure at the end

of waiting two years how those answers will actually help

us to go one way or another -- this is just full

transparency, that’s what our thinking is -- but we still

wanted to give you that option as a recommendation choice.

34

So those are the four choices that we thought you

want to consider. I guess at this point in time how do we

want to do this? Should we go around?

DR. HERR: Do we have any anticipation of any

change in vaccine production from the manufacturers, in the

sense that we anticipate that RotaTeq is not going to be as

available as it has been in the past? Because we have had

this with other vaccines where all of a sudden they are not

making it. Or, do we anticipate any change in purchase in

the sense that VFC authorization, does VFC purchase now

both RotaTeq and Rotarix?

Or do we have a preference of one versus the

other? In the sense of, if the predominant use in this

country is RotaTeq and the increased risk is primarily

through what we know so far from the Mexican study is

Rotarix, are there things that we could do purchase wise?

That we would have VFC authorize only RotaTeq purchase

versus Rotarix that would modify that while we wait for the

study?

If the makeup of the vaccine use in this country

stays the same, we’re not really going to see much, and we

shouldn’t see as much. And that might in many ways still

be a safer, responsible thing to do while we look at more

information.

MS. PRON: What is the safety thing?

35

DR. HERR: The Rotarix, by the studies, is a

little bit riskier vaccine. And it may be just because of

the data and what data information we don’t have.

DR. JOHANN-LIANG: Right. If Mexico and Brazil

actually -- the manufacturers compete for the country to

buy, and Rotarix just won out, that was all. But if

RotaTeq had won out, who knows what the data would be,

right? So I totally know what you are saying.

In answer to your question, number one, do we

know if there have been any shortages for either

secondarily? Not that I know of. Do you know, Tom, from

CDC?

DR. HERR: Not that I know of.

DR. JOHANN-LIANG: We have talked to the

rotavirus people at CDC pretty recently. I don’t think

they anticipate there is going to be any shortage issues.

But you are right, we don’t know. Maybe there is some

contamination with RotaTeq and then Rotarix is available

and Rotarix gets the big uptake. Anything is possible.

But right now we don’t know anything in the future.

Number two, to answer your question about do we

know whether either one is preferred to be used, RotaTeq

came before Rotarix and that is why it sort of stayed.

DR. EVANS: Market share.

DR. JOHANN-LIANG: But according to CDC, although

36

I am not really sure what the exact information source for

them to say, but they do think that Rotarix, the company

will try to be more competitive as far as pricing, et

cetera, and they will try to market it in this country

more, and that the uptake of Rotarix will go up.

I don’t know what the timeframe is, but the

market share right now is mainly all RotaTeq and a little

bit of Rotarix. But over time, it will come up. Rotarix

will come up. That is their feeling. But I don’t really

know. This is company, probably financial information that

we are not privy to, so we don’t really know.

DR. HERR: Wouldn’t a responsible thing now be

for us, while we study, to put more governmental preference

on purchase of the safer vaccine? I mean again, it is not

our purview, so to speak, here, because we are talking

about the table. But again, our responsibility here is to

look at facts in utilization and safety of the vaccine.

DR. JOHANN-LIANG: Right, but I guess the general

thinking behind this is that you have the background of

RotaShield. You have two different second generation

vaccines. And granted that they are different, a

reassortment, et cetera, and we do think that we have more

information on Rotarix, but, again, that is because of who

studied it and what the denominator was.

We don’t really know whether there is a

37

difference in safety between these two vaccines. The data

is what we have. It really depends on how many people you

study in what sort of a population. The study does not

assure us that RotaTeq is safer than Rotarix, or Rotarix is

safer than RotaTeq or anything like that. We just don’t

have enough data to say.

But given the background of RotaShield, given the

Guiding Principles, we thought the best thing to do is to

give presumption of causation. Not that there is causation

per se, but presumption of causation for second generation

rotavirus vaccines in general, and propose to put that on

the table, with a qualification saying that if you have a

child with a lymphoma, if you have a child that had an

adenovirus infection within the right time, that that is

really not a qualifier for presumption. Because that would

be much more likely as an event to an IS than a rotavirus

vaccine.

So we are not saying one vaccine is safer than

the other, we’re saying we are kind of looking at it in

total. Does that make sense to you?

MS. HOIBERG: My question is, we talk about how

if the shot aggravates a pre-existing condition. Yet here,

you are excluding pre-existing conditions, children with

pre-existing conditions you are excluding from really it

being a presumption of causation, if I am using that

38

correctly.

It says onset in a person with a pre-existing

condition, which causes lead to intussusception, such as

intestinal masses and cystic structures. Who is to say

that the vaccine didn’t aggravate that condition?

DR. JOHANN-LIANG: It is really important to

remember that when we put something on a table it is a

presumption of causation. We are just saying, without

going through all the litigation, someone comes in with

intussusception within this timeframe, they get the

presumption, unless it’s blah blah blah blah.

That doesn’t mean -- what you are talking about

is an aggravation. We are not defining what would be an

aggravation to the underlying disorder. I mean, that just

gets way too -- but if you have a case and let’s say the

person has an underlying disorder and you get the vaccine,

we can still look at that and do causation in fact. It’s

not like we can’t give them compensation. Does that make

sense?

This is just saying, when you are presuming

something, when you are saying okay, nothing else, we look

at it, it meets the facts, go, we have to have certain

rules of engagement. That’s what we are laying out here.

And as I told you, the numbers, the naturally occurring

intussusception as opposed to the possible small

39

attributable risk from second generation rotavirus, it

can’t be but that it’s these things, if somebody has a

clearly defined leading point, et cetera. That’s what

would define the qualification.

MS. JACOBS: Let me just add something. So

Congress’ original table that they created, it did the same

thing. They basically inserted exclusions of basically

pre-existing conditions. So it’s not like the program is

trying to do this de novo. So they have precedence for

that.

MR. JASON SMITH: The QAI, the first presumption

is the onset occurs after the third dose of the rotavirus

vaccine?

MS. SAINDON: No, that’s the opposite. That is

an exclusion.

MR. JASON SMITH: Exclusion, I’m sorry, I said it

the wrong way. So in other words that would not be a

presumption of causation.

DR. JOHANN-LIANG: The studies actually showed

that when you look at the total, there doesn’t seem to be

any difference in the incidence of intussusception of kids,

looking at the first year. So it looks like there may be a

small attributable increased risk for the first dose,

definitely. Maybe the second dose. We are just doing that

as a Guiding Principle, give the second dose.

40

But the third dose, the data really looks like it

may be protective, which is just to say that at the end of

the year everybody sort of ends up in the same place. So

for us to say that would be a presumption of causation,

would be really too much of a stretch. So that’s why it’s

not --

MR. JASON SMITH: It is? So you feel comfortable

that the data is supporting this exclusion from a

presumption --

DR. JOHANN-LIANG: Yes.

MR. JASON SMITH: Okay.

DR. JOHANN-LIANG: Dr. Smith, Candace? Are you

on the call?

DR. CANDACE SMITH: Hi.

DR. JOHANN-LIANG: On the West Coast. Do you

want to elaborate a little bit more on the third dose

issue? That is a question that came up.

DR. CANDACE SMITH: We have a study. Even from

the very beginning, the pre-marketing studies, it looks

like we were protective at the end of a year. You know, as

they did those pre-marketing studies they looked at the end

of a year and they were very protective against

intussusception. So as the post-marketing studies have

gone on, they have actually looked at first dose, second

dose, third dose, the risk with each one.

41

And what they noticed is that the risk is well

below one. Which means that it is protective by the third

dose. I think the most recent data is that you are at a

risk of .2, and a risk of one is, all things being equal,

there is no risk. So when you get to a risk of .2, that

means you are actually more likely to be protected against

intussusception than to get an intussusception after a

third dose.

And the reasoning behind that is, I guess the

best way to say it is the vaccine has kind of primed your

intestine and protected it against it. So that if you were

to have some sort of trigger for an intussusception, your

intestine is now primed and it is not going to have it. I

hope that makes sense.

MR. JASON SMITH: So it did show then, with each

administration of the vaccine the relative risk decreases

from first, second, third?

DR. CANDACE SMITH: Yes, we drop a lot. So I

think the Australian data was the most important. The

first dose was a relative risk of about five, the second

one was about 1.5, and the third one was .2.

DR. JOHANN-LIANG: So it would be very hard for

us to do that as a presumption. So that is why it would be

very hard for us to put that, just lump it all together.

We really struggle with this. We really think that this

42

is, under the Guiding Principles, the most generous way to

do it, including the second dose into the presumption, but

really making sure that we say, a third dose, if the

vaccine is actually protective, we don’t want to say that

is presumptively causal for intussusception.

DR. CANDACE SMITH: And I think it is important

to also say that just the natural intussusception, that

third dose time is the time when you should be at the

highest risk, the peak time for intussusception. So it is

really remarkable that you are seeing such a drop in the

people who receive their rotavirus vaccine, for that timing

of the third dose. So the science definitely points to the

third dose as protective.

DR. DOUGLAS: You noted a one in 100,000

occurrence. How does that match up against other injuries

in the table?

DR. JOHANN-LIANG: That’s a good question. Was

GBS, if you look at GBS, in the background, it is probably

one in 100,000. So that would be like a natural GBS

occurring. So that’s not on the table, but I am just

trying to think about the things, the claims that were

coming in. Thrombocytopenia, about one in 50,000, one in

40,000.

PARTICIPANT: So this is good. This is very

good.

43

DR. JOHANN-LIANG: This is very, very low risk.

We had a discussion about even mitochondrial incidents.

This is just diseases. We are talking about some things on

the table. And something in one in 4,000, that’s what he

was talking about. So we are talking about a very, very,

very small risk.

MR. DAVID KING: That would be 10 in a million

though, right?

DR. JOHANN-LIANG: Right.

MR. DAVID KING: And how many vaccines are

administered?

DR. JOHANN-LIANG: For rotavirus?

DR. CANDACE SMITH: About 30 million to date.

For RotaTeq, right?

DR. JOHANN-LIANG: 30 million, Candace, or less?

DR. CANDACE SMITH: Sorry, I didn’t hear that.

DR. JOHANN-LIANG: For RotaTeq.

(overlapping voices, off microphone)

DR. JOHANN-LIANG: 30 million. Flu is what, like

160 million last year, per year. I don’t want to give

numbers without actually having it in front of me. And I

have that data, so again, get that to me.

MR. DAVID KING: On the actual number of vaccines

that are given.

DR. JOHANN-LIANG: Distributed.

44

MR. DAVID KING: Distributed, right. We don’t

actually know how many are given. We have gone through

that, yes, I remember that.

MS. PRON: My question is, if we decide to go

with the proposed amendment and the study that comes out

suggests something different, which may be not for another

two years before we really get the final count and we

decide it’s really going to say what we want, we can change

it again, right?

DR. JOHANN-LIANG: Yes. But it is about two

years to go. So that’s a question. We could wait. If it

was a claim that is coming in a lot it may be really nice

to have a presumption so we could move cases along. But as

I have shown you, the experience, it is not a huge number

of claims.

So we could wait. That is one of the choices

that we have, wait for the study to come in. The other

side of that is that there is no assurance that that study

will be definitive, either. We may still be uncertain at

that point.

MR. DAVID KING: I know there’s not a great

number of claims. But based upon current data in terms of

the number of claims that we have, a third of those claims

are occurring after the third dose.

DR. JOHANN-LIANG: Third dose, yes.

45

MR. DAVID KING: Right. And we are excluding the

third dose here.

MS. PRON: That’s just for the automatic, you

know.

DR. JOHANN-LIANG: That’s a presumption of

causation.

MS. PRON: Presumption of causality. It doesn’t

mean that they are not going to get compensated down the

line.

MR. DAVID KING: Understood. But I would suspect

that if it isn’t on the table, the case would be made if

one were to say. they’d say, well, it’s not on the table.

I think it will be a lot harder for someone to make their

case if the table doesn’t reflect it. It makes it more

difficult for the petitioner.

And, since we are supposed to be, according to

the Guiding Principles, more aligned with weighing more

heavily on the petitioner’s side of the table than on the

other side of the table, that we would --

DR. JOHANN-LIANG: But you have to have some sort

of a -- you are not just going to, everybody who has an IS,

you are not going to be compensating. You want to try to

tease out who possibly is injured due to vaccine, and want

to be very generous about that. That’s, i.e., the

interval, the dose, the second dose, et cetera.

46

But if the vaccine really looks like it is

something that is protective against an adverse event

following that dose, it would really not be -- it doesn’t

make sense to say --

MR. DAVID KING: No, we might not know. The

research is not 100 percent complete. And we don’t have

the adjudication of these claims yet, so there is no

determination yet, I suspect, on a third of the claims

already that are saying that it happens after dose five.

DR. JOHANN-LIANG: Dose three?

MR. DAVID KING: Dose three, excuse me. So there

are questions. I am afraid to rush into decision-making

here without some lengthy understanding discussion related

around to things that answer, like, the number of vaccines.

The Vaccine Information Statement that currently exists

would be useful for us to be reviewing, so that we could

compare it in case there is anything here that might --

So there is a lot of information, I think, that

we would still need to have to have a conversation about,

before we rush to any judgment. So I am thinking more in

terms of cautiously moving forward, but I am not yet

prepared to throw a motion out on the table here on that,

because I think we should discuss this a little bit

further.

MS. DREW: I am in agreement with Dave, but I

47

need a little clarification on B, where we have onset

within one month after an infectious disease. Does that

mean any infectious disease? Does that mean a child who is

vaccinated while he’s got the sniffles isn’t going to be

covered under this? I don’t really know what that means.

DR. RUBIN: The qualification has the examples,

as I have talked about and discussed, that the main

infectious diseases were the viral diseases and the

bacterial enteritis, and also parasitic infections.

MS. DREW: But what it says is, an infectious

disease, including -- and then it goes on to say without

regard to whether the organism of the infectious disease is

known. The way I read that is, if the child has any

infectious disease including the sniffles, which we can

probably presume is a virus, when the child is immunized,

that is within a month, that child is not going to be

subject to the table. It is not going to be a table

injury.

DR. RUBIN: When a claim comes to our program,

the medical reviewers do review this. Most of the time all

of us are really, we would do a literature search. And

most of the literature doesn’t necessarily show a strong

association with just, as you call it, the sniffles.

MS. DREW: But that is what the statute is going

to say. Irrespective of what your review may show, this is

48

what the statute says. So maybe that needs to be reworked

and make it clear that you are talking about something

intestinal as opposed to what it says now. I’ve got a real

issue with that.

DR. JOHANN-LIANG: When you look at the

literature, mainly the one month comes from exactly what is

listed there, which is the antiviral disease, which

actually is not just enteric antiviral disease but can be a

systemic antiviral disease. Some of the bacterial

enteritis, as well as parasitic infestations of the gut,

basically. And they are acting like a lead point, which we

don’t really see in the US very much.

So if the concern is that the language is too

broad so that it may make things like viral infections,

upper respiratory tract infections as an alternate factor,

then that’s something we can try to -- yes, we are open to

that. We are talking about infectious diseases that really

we know as causal for intussusception, that is well known

to be causal for intussusception.

There is a lot of literature even on using

antibiotics could be intussusception association, or ear

infections. So those are not what we were thinking of as

we were listing the --

MS. DREW: Also the word, within one month. Is

this within a month of the first manifestation of an

49

enteric disease? Or within a month after it is over? This

is so vague that I can just see all kinds of litigation

being sparked by this, litigation that isn’t necessary if

you folks clarify it before you put it into the statute.

MS. WILLIAMS: This is Michelle Williams. Are

there additional studies other than the PRISM study? Are

there still post marketing studies going on?

DR. JOHANN-LIANG: My understanding is that VSD

study, which is a US study that was presented at ACIP in

2010, it is kind of closed. And they are either preparing

or have already prepared for publication. And the

denominator for that, again -- and it’s mainly RotaTeq,

because it is US-based -- the denominator for that is just

under a million.

They see nothing. There is no attributable risk

at all in the US to the RotaTeq vaccine. Now I don’t know,

because it is not published, but this is personal

communication with the CDC person. So that is pretty much

done. It is my understanding in the US.

There is probably other, outside the United

States ongoing, with surveillance, et cetera, particularly

in Australia. I think that there is an ongoing study in

Australia with rather than doing -- remember I told you the

Buttery study was really looking at intussusception

happening over the expected background from historical

50

background in different provinces of Australia.

The one that is ongoing, that’s my understanding,

is actually doing this more self controlled, which is

thought to be a better quality study. So the Australians

are ongoing. But in the US I believe, Michelle, the only

thing we have is the PRISM. And we wouldn’t have any

preliminary results until end of next year, at best.

MS. WILLIAMS: And you had said -- I’m trying to

get a timing question to go to Dave’s and Sherry’s

comments, trying to move forward but maybe get additional

information at the same time. You started your notice, you

are drafting your notice. And when would the notice have

to go in? If we were to vote on it, when would the notice

go in? Would we see that notice before it got published?

DR. JOHANN-LIANG: Sure.

DR. EVANS: You will vote and make a

recommendation to the Secretary, and that will be taken

under consideration with the Department, and then the

notice will be published. And, as everyone else will, you

will have public comment, a six-month period of public

comment in which it can further be amended. And it will be

in the form of a final report.

MS. WILLIAMS: That was my question. If we voted

now and then the Notice of Proposed Rulemaking would be

drafted. But if there was additional information that

51

Sherry and Dave think need to be elicited, that would be

able to be done at the same time? Or would that require a

new recommendation?

DR. EVANS: It can always be adjusted and

tweaked, but there wouldn’t be a formal -- at least we have

not done that in the past -- a formal reconsideration

before it is published. But again, there can always be

changes after it is published because that is the whole

purpose of public comment.

MS. WILLIAMS: Just to try to figure out if we

are kicking the can or if we are going to expand or if we

are going to delay, if there is additional information that

could be incorporated into the Notice of Proposed

Rulemaking as comments?

DR. JOHANN-LIANG: Right. The Notice of Proposed

Rulemaking, it will take us some time to get that draft

together even though we have started drafting it. It’s a

regulation. It has to go through multiple clearances

through the agencies. That’s going to all take time. 2012

is an election year, we have been told. So any rulemaking

will take time.

We don’t want to delay too much. But let’s say

that during the process of proposing to NPRM -- and we can

always make changes, of course. And then even when the

NPRM goes out, it goes out for six months for public

52

comment and everybody is free to comment. That’s what we

are supposed to do, the Secretary, and hearing.

MS. SAINDON: Just to clarify one other thing.

By law you have 90 days. So you do not need to --

MR. DAVID KING: I was going to get a

clarification on that from you, if I could. On the slide

it says at least 90 days. So do we have more than 90 days?

Or do we only have 90 days?

MS. SAINDON: I think we can cut it off at 90

days, because the Secretary has --

MR. DAVID KING: That doesn’t answer my question

actually, if we can cut it off at 90 days.

MS. SAINDON: 90 days, you have 90 days.

MR. DAVID KING: So the at least 90 days is an

incorrect statement on the slide?

DR. JACOBS: No. It says the Secretary has to

afford the ACCV at least 90 days. So if they afford you 90

days --

MR. DAVID KING: Then they can do what they want.

DR. JACOBS: Yes.

MR. DAVID KING: Thank you. Now I have the

understanding, thank you, perfect. So we would have till

March 9th? Is that accurate? Or because we do have 29

days in February --

DR. JOHANN-LIANG: I don’t know, we have to look

53

at the calendar. Is that including business days or

weekends?

DR. JACOBS: I guess not. 90 days is 90 days.

MR. DAVID KING: That’s what I would do, 90 days.

So we meet on March 8th, and on March 9th. So we would be

within the timeframe of the statute, to be able to give a

recommendation if we were to review this at the next

meeting, say. And it might be more than a 15-minute

conversation.

DR. EVANS: Your comfort level is what is

paramount. If you need additional time to consider this,

that’s fine.

DR. JOHANN-LIANG: And that’s your choice here.

If you’d like to review the proposal.

MR. DAVID KING: This is one man’s opinion,

though.

MS. PRON: At least in my understanding -- I need

clarification here if it’s not correct -- this is Ann Pron,

for the people on the phone. Currently rotavirus, there is

no table of injury for rotavirus. So in fact, by adding

this, at least we are helping some folks, some parents, to

move along quicker. But if we don’t add it, everyone has

to go through the long process. Am I correct?

DR. JOHANN-LIANG: Yes, that is correct.

MS. PRON: So it may be in the future, if more

54

data -- because right now the data for dose three is not

really meaningful. There is not really anything in their

research that showed that there is an association between

dose three and intussusception. In fact, it goes in

reverse is what they are saying. It is a decrease in

intussusception after dose three rather than an increase in

cases.

So that if we pass this, in some ways we are

erring on the side of helping families rather than setting

up obstacles. That’s my read. Is that accurate?

MR. DAVID KING: I think that is one

interpretation. But I think that we may also be impeding

if we move too quickly because of the wording that Sherry

has brought up, in terms of what specifically does that

mean. So I think that we may be creating a litigation

nightmare and dragging things out. But I do think that we

need to be sensitive, though, to the fact that nothing is

on the table.

So I have a couple of questions, then, that will

help me in my thinking here. One of the questions is, if

we were to not wait till the next meeting to do this, and

to do this today, what material difference would that make

to getting it onto the table, as opposed to waiting till

March 8th or 9th?

In terms of what is the real timeframe, is it

55

going to make any significant difference? Or is it still

going to be the same time period?

DR. JOHANN-LIANG: It is really unclear, because

the timing of clearances is really not in our control. But

I can tell you that you guys have a lot of work ahead of

you with IOM. We are working really hard to try to bring

stuff to you next year, so we have got a lot of work to do

to move things forward.

The idea behind this is to take a program that is

so much off table, and so as you heard yesterday there is a

lot of litigation involved, to try as best we can with the

current size, with the Guiding Principles in mind, to add

things to the table so that we could give presumption of

causation. The medical folks are all here for presumption

of causation. That will really cut down on the time clock,

and we want to move things forward.

So the idea of waiting is fine. That is one of

the choices that we have, because it really is up to your

recommendation as to what you want to do. But I think next

year, personally, we are going to be in a lot of time

crunch. I am not sure. This is off of IOM, and we have

these signals from outside of the US coming in. We should

try to bring this to you. But it is really up to you.

MS. WILLIAMS: Let me ask another timing

question, then. Would your Notice of Proposed Rulemaking

56

go in to start the clearance process before our next

meeting?

DR. JOHANN-LIANG: We would like to.

DR. EVANS: To add on to what Rosemary said, in a

shorter version, the IOM track is going to be thick, long,

wide, lots of things on it. We had the perhaps idealistic

notion that we could have a quick, narrow short track to

get this done, as separate, get it within the Department

and they could clear it sooner, and not be as involved as

we are facing with the other rulemaking. And we got the

agreement to do it that way, which is a little different.

Normally people like to lump things together and

just do it all at once. We said no, this is different,

this was not IOM, and we think this is much more condensed

and simplified. But, as a great philosopher once said,

nothing is ever simple. I think the questions raised today

are legitimate questions, if somehow we can come to some

agreement and some answers. But if this could go forward

sooner than later I think it is better.

DR. FEEMSTER: I have one question about the

data. One thing that I noticed, for RotaShield the rule

very specifically referred to rhesus-containing, they

really talked about the components of the vaccine. This

time it doesn’t. Really, the data is quite different.

There is some suggestion that we may or may not end up

57

finding a definitive signal as studies are ongoing,

particularly in the US, for RotaTeq.

Was there any thought about -- I am not saying

that we shouldn’t add this to the table -- but about being

specific about the vaccine components? Because if down the

line, the PRISM study doesn’t show a signal with RotaTeq,

for example and we may make a decision to change the rule.

But Rotarix -- I mean, they are both quite

different, and you could argue that they may act a little

bit differently in the gut. One is human-based, one is

bovine-based. I just wondered if that was something that

you did talk about, because it was so specific with

RotaShield.

DR. JOHANN-LIANG: That is a very good point.

DR. FEEMSTER: And the data, especially now that

I hear that the Buttery study was comparing historical

data, that really makes it less powerful in my mind, if we

are weighing the strength of evidence.

DR. JOHANN-LIANG: I have to tell you,

preliminary data, although nothing is published yet, of the

self-controlled, the better, it seems to be in line with

what they have already shown. It is not contradictory.

Yes, Dave, go ahead.

MR. DAVID KING: So --

DR. JOHANN-LIANG: This is in regards to her

58

query, right? Otherwise I am going to respond and then you

can say.

MR. DAVID KING: You are going to respond to the

query here?

DR. JOHANN-LIANG: Yes, are you responding to her

query?

MR. DAVID KING: No.

DR. JOHANN-LIANG: Can I just respond to it then?

You are absolutely right. We could do what we did before

with the RotaShield, which is, you leave the rotavirus

vaccine blank, and then add another row that specifically

says only for the RV1 or the human-based, whatever. Not

the bovine-based, but the human-based. We could do that.

But the struggle that we had was, because Rotarix

is underutilized in the US, although we don’t know what the

uptake will be, we don’t even have one claim for it

actually. So we decided that, let’s say that Rotarix,

RotaShield, that’s two of three vaccines already, why don’t

we just do the general characteristics? Again, applying

the general principle. We are trying to be overly generous

at every turn here.

DR. FEEMSTER: I can see that. It’s just there

seems to be such a differential at least. It seems like

the stronger data is associated with the bovine-based

vaccine. But I understand that as well.

59

DR. JOHANN-LIANG: You see it’s a lot of levels.

DR. FEEMSTER: It’s not easy.

MR. DAVID KING: So there is a consensus I think

that we want to do something because we should. The

question is on timing. But there may be a way to make the

timing happen. Could there be changes made to the proposal

now, as we are speaking, that incorporated the concerns

that Sherry raised?

In other words, can we change the wording of this

right here and do some things along that nature to tweak

this as we sit in this meeting, it changes it, and then we

might be able to give you something that you can move with

today?

DR. JOHANN-LIANG: I am not sure if time is going

to allow us to word something right now. If they vote to

move this forward, can we have them make comments to the --

MS. SAINDON: Yes, the law requires, we are

seeking your comments and your recommendations. So if your

recommendation is to move forward and incorporate as many

of your comments as we can reasonably do, that is a totally

reasonable recommendation.

MR. JASON SMITH: Dave, can I suggest along the

same lines -- and I am in complete agreement, I think

Sherry’s concerns are good ones. Could we possibly

recommend that we move forward, but ask the Secretary to

60

consider some of the concerns raised by Sherry so that it

doesn’t appear to be from a language standpoint overly

restrictive in terms of that Paragraph B?

DR. JOHANN-LIANG: And that is precisely why we

provided you with all the references that we use for each

qualification, so that you can actually take a look and see

what your thoughts are on the matter. So we really welcome

that. That is why we are asking.

But as far as recommending what you want to do,

if you are concerned that if you recommend to move this

forward now it has got to go exactly the way it is, it is

going to take a lot of time to get it to --

DR. HERR: You can’t change any words at all on

it.

DR. EVANS: No, of course you can. In other

words, specify the kinds of changes you would like to make.

DR. JOHANN-LIANG: I didn’t hear what Tom said.

DR. HERR: I was just, you were making the

statement, it has to go as it is.

DR. JOHANN-LIANG: No. The recommendation is to

say, we want to do the table change. And I think what I am

hearing relevant to this is, that we welcome, and that’s

why we provided you with every slide with the references,

et cetera.

MR. DAVID KING: Just so I understand, because I

61

don’t want a motion to get on the table and we all go down

the road with a motion that we think means something but it

means something else. So before we make those motions,

let’s very quickly make sure we understand what we are

talking about here.

Which is, if we were to recommend that we wanted

to go forward with the change to the table, could we in

that recommendation specifically state, subject to certain

changes in this, and then that would then be the

recommendation so that it would be the recommendation is

that we want some of these changes? Can that be done?

DR. EVANS: Yes. For example, the Commission

years ago voted to add GBS for tetanus vaccine and for the

Secretary to develop an Aids to Interpretation to

accurately identify cases of vaccine-related GBS. Well

that was not possible, and the Secretary decided not to add

GBS to the table. That was the ACCV’s recommendation. The

Secretary didn’t take it. So you can recommend --

MS. SAINDON: But your recommendations will be

included in the preamble to the Notice of Proposed

Rulemaking, and we take them very seriously. So we are

seeking your comments.

MS. WILLIAMS: I think Dave’s question is, will

the Notice of Proposed Rulemaking have this paragraph just

the way it is? Or will the Notice of Proposed Rulemaking

62

be changed to have the paragraph be changed?

DR. EVANS: It is likely to be changed, and it

may be changed in 100 percent the way that you all are

describing, or there may be variations on the theme. But

the point is, you are voting to both add something to the

table as well as comment and endorse changes to the Aids to

Interpretation that will describe the injury that is being

added to the table.

MR. DAVID KING: Which is not exactly the same

thing as making the actual change. Is that correct?

DR. EVANS: Yes, there are two things. You are

adding under the general category of rotavirus vaccines,

you are adding intussusception with an onset of zero to 21

days. That is the first recommendation. And then the

second would be pertaining to the Qualifications and Aids

to Interpretation.

DR. JOHANN-LIANG: I just want to add, though, if

we didn’t have the IOM things coming down the line, we may

have much more, just practically speaking, much more time.

But because we want to start tackling those things starting

the next ACCV meeting, as I told you in the beginning of

the slides, it would be helpful if you guys, for that

second motion, if there was some sort of a timeline that

you would bring your recommendations and suggestions and

comments to us.

63

So that we can try to do the NPRM, try to get

that out, at least before March. We can’t promise

anything, but we are really trying to move things forward.

Does that make sense? We don’t want to be just waiting.

It’s another way of saying that we really want to hear from

you and incorporate what you want to say to the NPRM. But

we do have timeframes here, for us to move forward.

MR. DAVID KING: There is a saying, though, haste

makes waste. Let us be careful.

DR. HERR: This really is simple. But in your

alternate underlying conditions, on your slide you thought

it was important enough and during your presentation, to

say inflammatory bowel disease. But it is not in the

statute recommendation changes. Should it be there?

DR. JOHANN-LIANG: The inflammatory bowel

disease, really to be complete. It is more adults that can

actually have something like intussusception, or bigger

people. Usually babies, babies at six months, really there

is no diagnosis of Crohn’s or ulcerative colitis. We

really geared it more towards that and that was the logic

behind it.

DR. HERR: I just thought, you thought enough of

it to put it on your slide.

DR. JOHANN-LIANG: I think she was trying to be

very comprehensive.

64

DR. HERR: Okay, that’s fine.

DR. DOUGLAS: But in terms of advocacy for

parents who are looking for remedy, the best move for them

would be to have this on the table.

DR. JOHANN-LIANG: We are always trying to see

what would be best. Because it will help the presumption

to move forward. We would be doing everything else the

same way we are doing right now. It will cut down on the

amount of time, but again, we really want to hear from you,

and this is really good, the discussion that we are having,

because there is a science and there is a policy, and then

there is the patient advocacy. And those all have to kind

of merge.

That’s what is very different about this, that

pure science will logically say, we wait. But the program

and what our goals are, is a little bit different than

that. It is more over-arching than that. So that is why

we have before you. If it was purely left up to science,

Dr. Tom, we would wait. Right? Absolutely.

DR. HERR: This is Tom Herr. I would like to

move that we approve it.

MS. PRON: I will second it.

MS. WILLIAMS: When you say I approve it, I don’t

know what it is.

MR. DAVID KING: Your motion is to approve

65

exactly --

DR. HERR: As distributed. With the underlying

assumption, a realization that the Secretary can change

this as she wants.

(overlapping voices)

DR. HERR: What we are doing is approving that we

would like to move forward on the issue. And the issue is

to make a table of injuries, to facilitate taking care of

the kids who have qualifications specified on the table.

And move it on.

If there are some things that are sort of in

between the need to be fixed, that can be done. And the

assumption is that the Secretary will do that. And if it

doesn’t, it will come back and people will argue about it,

and we will say we want more.

MR. DAVID KING: So there is a motion on the

table that was seconded. So we should vote on that.

(Whereupon, the motion to go forward with the

recommendations for a change to the Table, with the

understanding that comments have been made concerning

wording on the Aids and Qualifications, and with the hope

that the Secretary will re-read the wording and consider

the suggestions and comments made by the Commission, was

duly seconded and unanimously approved.)

DR. HERR: We don’t need the second motion based

66

on that.

DR. JOHANN-LIANG: That is perfect.

MR. JASON SMITH: Sherry, can I just add one

other suggestion, just as a general commentary to some of

the language?

MS. DREW: Please.

MR. JASON SMITH: With various other vaccines on

the table, and some of the injuries listed, there is a

section, Section C, for example, for vaccines containing

tetanus toxoid, vaccines containing wholesale pertussis,

Section C, where it is this generic language about any

acute complication, the sequelae of an illness, disability,

injury. Sort of along the lines that Sara suggested

before.

It seems that it is listed for every injury

except for this vaccine. If we can also suggest that the

Secretary consider that.

DR. JOHANN-LIANG: Very good. So we really look

forward to -- it is very helpful to have people’s comments,

second look, third look. Do you guys want to have a

general discussion about when you want to bring the

comments to the Secretary?

DR. EVANS: The comments are on the record. We

will look at the transcript.

DR. JOHANN-LIANG: There is nothing else?

67

DR. EVANS: There is nothing else we need to do.

MR. DAVID KING: The only thing is that when we

talk about the Vaccine Information Statements, I would

think that where they talk about when can you get it, or

who should not get it, or things like that, it should be

consistent with the wording that you have in here, with all

that. That is really what we are talking about.

DR. JOHANN-LIANG: Those are good comments.

MS. PRON: That would be for the next agenda, for

the next meeting maybe, to re-review the rotavirus? Is

that what you want to do?

MR. DAVID KING: No.

MS. DREW: No, the VIS.

MR. DAVID KING: Oh, the VIS, to review the VIS

on it?

MS. PRON: Because that is what you are making

reference to, the VIS now?

MR. DAVID KING: Yes, but that was more in terms

of the actual comments on it.

MS. PRON: But I don’t think we can add anything

unless we come here.

MS. DREW: We are running really late. So I

think we need to move on.

(Brief recess)

Agenda Item: Update on the Immunization Safety

68

Office (ISO), Centers for Disease Control and Prevention

(CDC) Vaccine Activities, Dr. Tom Shimabukuro, CDC

DR. SHIMABUKURO: In the interests of time, I

will move through my presentation fairly quickly. But

before I start I just want to acknowledge the contributions

of Dr. Jane Gidudu, who is my predecessor. I am pretty

sure that I will be here with everyone who is going to be

on ACCV three-year terms before I eventually rotate off as

well. But it is a pleasure to join you.

One update which I don’t have on my slides, I was

able to confirm yesterday that there is a clinical trial

going on. It is called Immune Responses in Adults to

Revaccination with Adacel 10 Years After Previous Dose. So

that work is underway, to look at that as a 10-year

booster.

I am going to cover some highlights from the

October ACIP meeting. The two I will is the Gardasil

safety review and the ACIP vote. And then just an update

on the VSD febrile seizure investigation. I would just

mention our role in supporting HRSA in the IOM-generated

task force, and then some recent selected publications.

There was a very extensive review of Gardasil

during the last October ACIP meeting, which was the lead in

to the vote on males. And the data sources for this review

were from pre-licensure studies, data from VAERS for both

69

males and females, data from vaccine rapid cycle analysis

in females, and then two manufacturer sponsored studies.

This is the Nordic long-term follow-up study, and the long

term study of Gardasil in adolescents.

That information was presented during a previous

ACIP meeting, and that is available. Actually this

presentation, this comprehensive review and those two

manufacturer sponsored studies, those presentations are

available on the ACIP website. I am actually not going to

go into details. I recommend you do look at the Gardasil

Safety Review by Julianne Gee, an epidemiologist in our

office. It is very thorough.

Before I get into this actual summary, I will

just say that there was data presented on males

specifically in Julianne’s presentation, because there was

a vote on males. And just going through some of the

numbers there is a total of 569 reports for males, and most

of these over 500 were post-licensure reports. So there

were a few pre-licensure reports in there.

The breakdown for serious and non-serious is

roughly 94 percent non-serious and six percent serious.

That is consistent with what we see in VAERS. If you

looked at what we call the MedDRA Preferred Terms -- so

these are codes we look at in VAERS, they are not mutually

exclusive, so an individual could be coded to have multiple

70

MedDRA Preferred Terms with a single report -- for serious

reports we did not see any pattern, which is reassuring.

There were two death reports, verified death

reports for males. One was a case of myocarditis in a 10-

year-old with no past medical history. The other was a

death in a 15-year-old, 25 days after vaccination, who had

a known congenital heart disease. This is all available on

the ACIP presentation, which is on line at the ACIP site.

So no new adverse event concerns or clinical patterns were

identified in this VAERS review.

The VSD rapid cycle analysis confirmed no

significant risks for pre-specified adverse events after

vaccination for females nine to 17 years and 18 to 26

years. You can see the pre-specified adverse events there.

Of note in the VSD rapid cycle analysis study, there was a

non statistically significant increase relative risk for

venous thromboembolism among nine to 17 year old females.

This study was just in females.

It is important to note that there was a pattern

that many of these cases had known risk factors for VTE,

like obesity, smoking, oral contraceptive use. Which is

not to say that the vaccine couldn’t have aggravated an

underlying condition. But there is further work in VSD to

assess this finding, to include looking at other vaccines

other than just HPV4.

71

Further evaluation of VTE post-vaccination is

ongoing through other studies. And the long-term follow up

of adolescents have not identified any safety concerns.

Those are from the two manufacturer studies.

So ACIP voted on vaccination for males, and their

vote was a routine recommendation for HPV4 for males 11 to

12 years. And this series can start as early as nine years

of age. Males age 13 to 21 years who have not been

vaccinated should be given catch up vaccination. And males

22 to 26 may be vaccinated, but there is not a

recommendation for routine use.

Moving on to the VSD febrile seizure

investigation, I know Jane briefed you on this

investigation. So the previous flu season, 2010, 2011, VSD

was monitoring nine outcomes, to include seizures. And

looking at inpatient and emergency department settings,

because the coding for outpatient seizures in VSD is not

really good. But the coding for inpatient, the positive

predictive value, is fairly high.

So VSD detected a possible increased risk of

febrile seizures on days zero to one, post vaccination, in

this age group, six to 59 months, who received a first dose

of TIV. After chart review and confirmation, it looked

like the risk was highest in the six to 23 month age group.

And most had received other vaccines, most commonly

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pneumococcal conjugate vaccine and DTaP.

So the VSD investigators in CDC have presented

this a couple of times to ACIP. And what you see here on

this chart is actually the updated, what we think is going

to be the final updated results. This has been

provisionally accepted, this paper is provisionally

accepted to the journal Vaccine, and hopefully will be

published fairly soon.

What the investigators did for reasons which are

more into statistical methodology, they transitioned from

an age stratified analysis, to a statistical model. So

previously you may have seen these breakdowns -- six to 11

months, 12 to 23, 24 to 59 -- and seen the relative risks

in those age groups. And the decision was made to go with

a statistical model looking at the entire age group, but it

really didn’t change the bottom line.

As you can see here, there is a slight increased

risk in febrile seizures in this age interval for

inactivated influenza vaccine, without pneumococcal

conjugate vaccine. That is also plus or minus other

vaccines. And also a slight increased risk for PCV13,

without TIV, but with other vaccines.

But really the risk is highest when TIV was given

concomitantly with PCV13, and other vaccines, still in this

roughly 12 to 23 month age group, peaking at about 16

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months of age at an attributable risk of 45 per 100,000.

If you flip that over that is about, in the age group, one

additional febrile seizure for every 2,000 to 3,000

vaccines administered.

So the recommendations after CDC and ACIP looked

at this, was that there are no changes in the immunization

schedule that were necessary at this time; giving

recommended childhood vaccines during a single health care

visit has important health benefits, and timely vaccination

can prevent influenza and pneumococcal disease and may

actually prevent febrile seizures from fevers from these

infections.

In our communications piece we also noted that

scientific evidence -- scientific studies have not shown

that fever reducing medicines like Tylenol or Motrin

prevent febrile seizures. So there is no recommendation to

use those prophylactically. And of course aspirin and

aspirin containing products should not be used to reduce

fever in children, because of the increase in Reye

Syndrome. There is a more comprehensive study underway in

the Vaccine Safety Datalink to assess febrile seizures in

general, and the contribution of other vaccines.

So I just want to point out that we have 16 ISO

staff that are currently supporting HRSA as members of this

task force that is reviewing the IOM report and generating

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recommendations to update the Vaccine Injury Table.

A couple of quick notes on publications. We

recently had a publication come out, Duderstadt et al.,

which looked at data in the defense medical surveillance

system. The bottom line on this study was there was no

increased risk of diagnosed type I diabetes in any of the

study vaccines. And you can see those vaccines there.

Some of those are not really used that much in the civilian

world.

We had a study come out from the Vaccine Safety

Datalink on wheezing lower respiratory disease and

vaccination of premature infants. And there was no

evidence of increased wheezing lower respiratory disease

following routine vaccinations of premature infants.

And wheezing lower respiratory disease among non-

fragile premature infants appeared to be reduced for a few

weeks after live attenuated vaccinations. This did not

include LAIV. These live vaccines were MMR, varicella, OPV

and I think those are the live vaccines they looked at.

The top paper is just the HPV4 VSD rapid cycle

analysis paper that I discussed. And then the last paper,

Huang et al, was a survey of physicians looking into really

knowledge, attitudes and behaviors around the ACIP

recommendations to prevent injuries from post-vaccination

syncope.

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And the take home message on this paper was that

few physicians are aware of the recommendations for post-

vaccination observation for syncope, and even fewer adhere

to them. So there is room for improvement in that arena.

That is all I have and I will be happy to answer questions

if you have any.

MS. DREW: Thank you. We are going to go out of

order a little bit on our agenda, and call for Dr. Salmon,

who needs to give his report, his update from the National

Vaccine Program Office as soon as possible. Dr. Salmon,

are you there?

Agenda Item: Update from the National Vaccine

Program Office (NVPO), Dr. Dan Salmon, NVPO

DR. SALMON: (off microphone) Yes, I am on the

line. Thank you for allowing me to go out of turn. I

appreciate it. The update that I give, I want to focus on

an upcoming NVAC, National Vaccine Advisory Committee

meeting February 7th and 8th.

PARTICIPANT: Can you speak a little louder?

DR. SALMON: Can you hear me okay?

PARTICIPANT: No.

MR. DAVID KING: Slowly and louder, please.

DR. SALMON: Let me try again. This is Dan

Salmon from the National Vaccine Program Office. The

update I would like to give is on our next NVAC meeting,

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the National Vaccine Advisory Committee, which gives advice

to the Assistant Secretary for Health on vaccine policy.

Our next meeting is February 7th and 8th. Can you hear me

okay now?

MS. DREW: Yes, thank you.

DR. SALMON: Okay, good. There are a number of

items on the agenda which I can go through briefly but I

think one in particular which will be of interest to this

group. So the draft agenda which is still being finalized

includes topics such as the Adult Immunization Working

Group Health Care Personnel Influenza Vaccine Subgroup,

discussions of 317 funds and vaccine financing.

There will be updates from each of the agencies

and liaisons. There will also be international discussion

of immunizations in the international arena. And lastly,

not on the agenda but in terms of what is most important to

this group, we expect to file a report from the Vaccine

Safety Risk Assessment Working Group.

The ACCV has heard of this group before. This

was the working group that was set up for H1N1, and it

looked at all the safety data from the many systems that

were monitoring the safety throughout the vaccine program.

At this point they have been reviewing all of the end of

season analyses.

They have put together a final report, which will

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be presented to and deliberated upon by the NVAC at the

February meeting. This will be a summary of what we know

about the 2009 H1N1 vaccine. Let me stop there, and I am

happy to answer any questions.

MS. DREW: No questions. Thank you Dr. Salmon.

DR. SALMON: Thank you.

MS. DREW: Is Dr. Barbara Mulach on the line?

DR. MULACH: Yes, I am here, and I am ready, if

you are ready for my update.

MS. DREW: Thank you. Just one second. You will

be giving an update on the National Institute of Allergy

and Infectious Diseases, National Institutes of Health and

Vaccine Activities. Thank you for waiting for us. We are

a little late, but please go ahead.

Agenda Item: Update on the National Institute of

Allergy and Infectious Diseases (NIAID), National

Institutes of Health (NIH) Vaccine Activities, Dr. Barbara

Mulach, NIAID, NIH

DR. MULACH: Sure. I just have one main thing

that I wanted to make sure that everyone was aware of. I

have spoken at previous ACCV meetings about the program

announcement that NIH and CDC co-sponsor. And that was

originally intended to expire in September, and then it was

extended through January.

In late November we were able to extend the

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program announcement for three more years, which is very

exciting. And so just to remind you a little bit about

what this program announcement entails, it is called

Research to Advance Vaccine Safety. And the purpose is to

support research that will contribute to the overall

understanding of vaccine safety, wherever there are

scientific questions, where we don’t have enough

information.

I wasn’t available for the full morning session

but I am sure that one of the topics that was discussed as

part of the IOM discussion is that there still are a lot of

scientific questions that need to be addressed. And this

is one way in which scientists can propose ideas for how to

get more information in that area. So like I said, this is

the second iteration of that announcement.

It was sort of slow in getting the attention of

scientists at first, but I am very encouraged by the number

of people who have shown interest in seeing this new

announcement that came out in late November. I am very

hopeful we will be able to encourage people to look at some

of the ideas in the IOM report, and propose ways to try to

address those questions and get us more answers.

I will be happy to send the links, for those who

are interested in seeing the announcement. Again, we are

sharing it with the scientific community as well.

79

MS. DREW: Thank you. Does anyone have any

questions or want the links? Thank you, Dr. Mulach.

Lieutenant Valerie Marshall is here to give an update on

the Center for Biologics, Evaluation and Research, Food and

Drug Administration Vaccine Activities.

Agenda Item: Update on the Center for Biologics,

Evaluation and Research (CBER), Food and Drug

Administration (FDA) Vaccine Activities, Lt. Valerie

Marshall, CBER, FDA

LT. MARSHALL: Good morning. My name is

Lieutenant Valerie Marshall. I will replace Dr. Marion

Gruber as the FDA representative to this committee. Marion

Gruber is currently the Acting Director of the Office of

Vaccines, Research and Review. The former director, Dr.

Norman Baylor, has since retired from the position as

director.

Since the last ACCV update of September 2, 2011,

there were no new original biologic license applications

approved. However, there are several vaccines currently

under review, including a vaccine to prevent infants age 2

to 16 months of age from meningococcal disease types A, C,

Y and W134 [SIC -- w135?], a vaccine to prevent

pneumococcal disease in adults 50 years and older, and an

influenza vaccine containing four strains.

The Vaccine and Related Biological Products

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Advisory Committee met on November 16, 2011 to discuss and

make recommendations on the safety and immunogenicity of

the pneumococcal 13-valent conjugate vaccine in adults,

aged 50 years and older, using an accelerated approval.

On September 16, 2011, the FDA and the National

Institutes of Health, the Institute for Allergy and

Infectious Diseases, held a public workshop entitled The

Development and Evaluation of Next Generation Smallpox

Vaccines. The purpose of the public workshop was to

identify and discuss the key issues related to the

development and evaluation of next generation smallpox

vaccines.

The workshop included presentations on the human

response to smallpox vaccines, and the development of

animal models for demonstration of effectiveness of next

generation smallpox vaccines. And that’s all I have for

FDA.

MS. DREW: Thank you very much, and welcome to

our meetings. We look forward to seeing you in the future.

LT. MARSHALL: Okay, thank you, my pleasure.

MS. DREW: That ends our presentations for the

day. Our next agenda item is the nomination and election

of a new Chair and Vice Chair for the Commission.

Agenda Item: Nomination/Election of New Chair and

Vice Chair, Ms. Sherry Drew, Chair

81

MS. DREW: Annie, do you have paper for us?

Paper ballots? I am not exactly sure how you want to

proceed with this. In the past we have had nominations

made and then just, if there was more than one nomination

we just made a secret vote. I don’t know if it will come

to that or not, but I am wondering if we could have

nominations for the Vice Chair now.

MS. HOIBERG: I would like to nominate Michelle

Williams.

DR. DOUGLAS: I would like to nominate Kristen.

MS. DREW: I don’t know if you want to say

anything. Hopefully the two nominees will be present for

most of the meetings. That’s probably the biggest

qualification. Do you want to say anything?

DR. FEEMSTER: I would be honored to serve as

Vice Chair and do plan to attend all upcoming meetings and

to work with the Chair to help make sure that we discuss

all that needs to be discussed and facilitate a smooth

meeting.

MS. DREW: Thank you. Michelle?

MS. WILLIAMS: The same. Top that. If asked to

serve I would be pleased to serve, and I do plan to attend

all the meetings.

MS. DREW: All right. Now we are looking for

nominees for the Chair.

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MS. HOIBERG: Dave King.

MS. DREW: Second?

(Seconded)

MS. DREW: Any other nominations? I think that

one is easy. And I don’t think we need a secret ballot,

given we have only one nominee. We still have to vote, but

I thought we could do a show of hands. Show of hands for

Dave?

(Show of hands -- unanimous.)

MS. DREW: Dave has been elected unanimously the

new Chair of the Commission. I will turn this over to you

in a minute. If you want to just write down Michelle or

Kristen.

PARTICIPANT: Do we have the same length of time

of service spanning? Are we on the same term?

MS. DREW: You serve for a year, or however long

you choose to serve. You just have to be elected. There

isn’t any real term.

(Paper ballots collected and tabulated)

MS. DREW: Michelle has been elected our Vice

Chair.

MS. WILLIAMS: And may I say it was an honor to

run against Kristen a worthy honor.

Agenda Item: Future Agenda Items, Ms. Sherry

Drew, Chair

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MS. DREW: I am still Chair here, and we are

looking for future agenda items now. Tom brought up a

subject yesterday, the packaging of vaccines, there should

also be something on the label. I think that needs some

further discussion. And I don’t even know who might

address that.

DR. EVANS: Well, we will work on it. It is

certainly an FDA issue. Also this issue of a CDC safety,

but also has some -- we will work with our colleagues on

that.

MS. DREW: Okay. Is there anything --

MS. PRON: It looks like we need something about

the VIS for rotavirus, possibly.

MS. DREW: Possibly the VIS for rotavirus.

MR. DAVID KING: Right. We need to determine

whether or not -- so the question I have on that, because I

do think that it needs to be reviewed, is, is it premature

to review it yet, though, if we don’t have it on the table?

So I don’t know if it is necessary for the next meeting or

not. I guess we need to figure that out.

MS. PRON: And we need to have an ongoing list of

things that will need to come up, even if it is not at the

next meeting.

MR. DAVID KING: I will do that. I’ll have that.

(laughs)

84

MS. WILLIAMS: There is no reason why it couldn’t

be included in the packet, even if we didn’t have --

MR. DAVID KING: I would agree. That’s fair.

DR. DOUGLAS(?): Most of the concerns are not

things that would be on the VIS. Most of the kind of

background concerns with the wording and the injury table,

that would not be on the VIS.

MR. DAVID KING: The future science meeting. Are

we going to have a report from them at the next meeting?

Michelle? Will there be a future science meeting report at

the next meeting?

MS. WILLIAMS: Yes, we can do that.

MS. DREW: All right, future science on the next

agenda.

MR. DAVID KING: There was one yesterday, wasn’t

there?

MS. WILLIAMS: That I didn’t attend.

(overlapping voices)

MS. DREW: I think now we need volunteers for the

agenda workgroup committee. Dave and Michelle will be on

it automatically. Probably we need one or two more folks

to meet once or twice prior to the next meeting to clarify

the agenda. Kristen? All right, Kristen will be on the

agenda meeting. Anybody else?

MS. PRON: I’m not sure how easy it will be for

85

me to call in. If it’s not hard, I will do it.

MR. DAVID KING: So why don’t we invite you, and

if you can make it, you will.

MS. DREW: And perhaps one of the new people

might even volunteer after they have been sworn in. They

could be drafted at that point.

MS. PRON: May I suggest another item then, for

the ongoing list on the agenda which we said from the

minutes? And I said it, but I wasn’t sure, because we were

all sort of talking at once. But injection practices,

changes to injection practices, recommendations about

changes to injection practices from the shoulder injury

reports that we had.

That was a carryover from the minutes from the

last time that we said we would talk about it, put it in as

an agenda item. But I don’t think we talked about it.

MS. DREW: Okay.

MR. SMITH: Maybe we could fold it into that

general topic during the CDC presentation, about this

concept of 15 minutes after the vaccination administration,

and if it is there to go ahead and try to educate more

about the importance of doing that, because of syncope. At

some point in the future, probably not the next meeting.

MS. PRON: Follow up to that research study that

you mentioned.

86

DR. HERR: We are currently doing analysis on

vaccine errors or administration injuries. Would you be

interested in just seeing the actual data on that? Or is

this more of an outreach? Are you more interested in

outreach and education to vaccinators and how to give

proper injections?

MS. PRON: I think that is an issue. That seems

to have come up in your study that the ACIP recommendation

hasn’t been implemented.

DR. SHIMABUKURO: You are talking about the

server paper?

MS. PRON: Yes. And the syncope issue.

DR. SHIMABUKURO: The way this works, this goes

through the ACIP General Recommendations Workgroup. And I

am actually on that workgroup. And this subject has come

up from time to time and there was no big light bulb that

went on with the servers so far, but that is certainly

something that we can pursue because that is recent

information.

Syncope they have discussed before. And as I

understand it, when you start making recommendations for

doing things it becomes a standard of care. And when it

becomes a standard of care, then it becomes possibly

something that involves litigation. So they are careful

about how prescriptive they are about how long and what you

87

are supposed to do, et cetera.

But this is something that is discussed.

Everyone is aware that there is certainly a risk in some

children and adults, of having syncope after vaccination.

It’s something that we can certainly bring back to the

General Recs Workgroup and just see what their current

thinking is, as far as this issue.

MS. WILLIAMS: Despite being a lawyer, I

recognize that it does become a standard of care. And then

ensuing civil litigation on a malpractice front. But that

is not our concern. Our concern is patient safety.

MS. SAINDON: In fact, the vaccine program covers

both vaccine administrators and manufacturers. So even if

it is the standard of care, the requirement would be that

they come to the VICP. So I think it is absolutely within

the purview.

DR. EVANS: This has been pointed out.

MS. PRON: Well, we have already compensated for

that, right?

DR. EVANS: And we have compensated, both

injection injuries as well as things like post-injection

syncope.

MS. WILLIAMS: Why shouldn’t it be a standard of

care?

DR. EVANS: And the practicalities of 15 minutes

88

in a busy clinic where there are very few places to wait

and so on. It’s a lot easier said than done when you put

it in a recommendation. So again, we will see what the

latest thinking is at the workgroup.

MS. HOIBERG: That goes back to what I have said

that the major problem is that the vaccines aren’t given

the respect that they deserve. They are given out just

really willy-nilly. And so especially with the flu vaccine

and all, I feel like there needs to be a step back and a

re-education of the practitioners and the people who are

giving out the vaccines, to be like, hey, listen, you need

to take care.

You are injecting something foreign into a body

and you don’t know how they are going to react, whether

they are going to faint, whether they are going to have a -

- you have got to be careful how you give it. They are not

careful. And so I think that re-education is something

that is very necessary.

DR. DOUGLAS: When I was an educator of the

initial practitioners, we take it very seriously. And

during my first meeting I noted that the large injuries

that come when you inject way up here, and my thought was,

no one in life has ever been taught to inject way up there.

So I just reiterated that we are educating properly initial

practitioners.

89

I know the older I get and the more gray hair I

have, the more babyish they look. And they look like

absolute children. But they graduate at 21 years old, and

professionals with a license. And we can’t call them

babies or honey or sweetie any more. (laughter)

And I have run clinics in malls and I have run

clinics in storefronts. And I have run clinics in

incredibly busy clinics and on military bases. We are

mindful. We have our little section with the little seats.

Especially even what I have learned here, just to reinforce

for me that if you shoot a teenager, they are going to drop

like a stone.

On that side of the table it is not a void, that

we are preparing people who must take a license, and they

must know. And so we are working very hard on that end.

MS. DREW: Any more future agenda items? Can we

go to public comment? Operator, do you have anybody

waiting for public comment?

Agenda Item: Public Comment

OPERATOR: We are showing no public comments at

this time.

MS. DREW: Thank you, the public comments session

is done. I think the meeting is complete.

DR. EVANS: What I wanted to do is just to

reflect on the sad fact that we are saying goodbye to three

90

people who have been part of the ACCV family for the last

three years, and I know at times probably they were going

to be part of the family for several generations -- Tom,

Sara and Sherry.

I was wondering if any of you would like to give

us some parting thoughts, as you sail off, ride off.

DR. HERR: It’s been a real honor and it’s been

an education to be here. I came in with certain

expectations and certain ideas about things. You learn,

you modify. So it’s important, it has been a growth in my

being in education. It has been well worth it.

And seeing people who work hard for this, and for

the kids and now adults in all phases, whether they be as

parents or whether they be as attorneys trying to fight for

them, or mobilizing the Justice Department, and Rosemary,

the things that they do to try to make things straight and

keep things in order.

It is a daunting task. As well as Geoff, trying

to keep all of us organized and keep himself in his job.

It is hard not being able to always realize what you are

trying to do and be fair to everybody. But it has been

something I have appreciated. Thank you very much.

MS. DREW: I agree with Tom. It has been an

education. I have always tried as an attorney to see both

sides to every issue. Here I have seen there has been at

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least 10 sides to every issue. I have enjoyed working with

the people here. I have made some very good friends, and I

thank you for bringing me on, Geoff. I will miss you guys.

MS. HOIBERG: It’s been fun. Very educational.

Just keep up the work.

DR. EVANS: Well, it’s auf wiedersehen, it’s not

goodbye. But there are various ways that you can help us,

and please stay in touch with the program. And maybe we

will have televideo, tele meetings in the future and you

can always, if you have the time, tune in.

You are one of the select few that has a

reasonably good understanding of what this is all about,

and a reasonably good understanding is quite a lot to say.

Because there is a lot to understand about this program and

its ins and outs and so on.

So when you hear someone make a comment about the

compensation program from what they have heard or read in

the paper, whatever, you have this insight. It will serve

us, as you can be our ambassador to try to help people

understand what it is we are trying to do, and trying to do

the best we can at it.

I want to particularly thank Annie. Give Annie a

round of applause. She really has been just great getting

everything together. She really singlehandedly has put all

this together with a smile on her face.

92

We have the business to adjourn and we also have

business after we adjourn.

Agenda Item: Adjournment of the ACCV December

Quarterly Meeting

MS. DREW: Do I hear a motion?

(Motion to adjourn)

MS. DREW: Do I hear a second?

(Seconded)

MS. DREW: The meeting is adjourned, I will bang

the hammer for the last time.

(Whereupon, at 11:45 p.m., the meeting was

adjourned.)